Evaluation of CD46 re-targeted adenoviral vectors for clinical ovarian cancer intraperitoneal therapy

Abstract

Ovarian cancer accounts for >140 000 deaths globally each year. Typically, disease is asymptomatic until an advanced, incurable stage. Although response to cytotoxic chemotherapy is frequently observed, resistance to conventional platinum-based therapies develop rapidly. Improved treatments are therefore urgently required. Virotherapy offers great potential for ovarian cancer, where the application of local, intraperitoneal delivery circumvents some of the limitations of intravenous strategies. To develop effective, adenovirus (Ad)-based platforms for ovarian cancer, we profiled the fluid and cellular components of patient ascites for factors known to influence adenoviral transduction. Levels of factor X (FX) and neutralizing antibodies (nAbs) in ascitic fluid were quantified and tumor cells were assessed for the expression of coxsackie virus and adenovirus receptor (CAR) and CD46. We show that clinical ascites contains significant levels of FX but consistently high CD46 expression. We therefore evaluated in vitro the relative transduction of epithelial ovarian cancers (EOCs) by Ad5 (via CAR) and Ad5 pseudotyped with the fiber of Ad35 (Ad5T*F35++) via CD46. Ad5T*F35++ achieved significantly increased transduction in comparison to Ad5 (P<0.001), independent of FX and nAb levels. We therefore propose selective transduction of CD46 over-expressing EOCs using re-targeted, Ad35-pseudotyped Ad vectors may represent a promising virotherapy for ovarian cancer.

Understanding and addressing barriers to successful adenovirus-based virotherapy for ovarian cancer

“…Moreover, Ad5/3-Δ24 demonstrated greater oncolytic effect compared to Ad5-Δ24RGD in cell lines, clinical tumor samples and in a intraperitoneal xenograft murine model [84,85], showing a good safety profile and potential in a phase I clinical trial [86]. In order to achieve higher transduction efficiency by using CD46, Hulin-Curtis et al pseudotyped Ad5 with the fiber of Ad35 [87,88] and was able to achieve higher transduction efficiency in EOC cells. Similar to Ad5-A20, a chimeric Ad5/48-A20 vector based on the low seroprevalent Ad48 was able to target primary ex vivo cultures in the presence of neutralizing ovarian ascites [77].…”

“…Since a small portion of the Ad particles injected ip are able to enter the circulation, Ad vectors administered through this route are susceptible to clearance after interacting with blood components and residential macrophages in tissue and in the peritoneal cavity [83,139]. It was first shown that modifications of the fiber partially ablate neutralization of the virus [77,78,84,140], and later, that additional pseudotyping of the hexon or the ablation of FX binding sites in the hexon decreases liver sequestration, toxicity and vectorimmune system interactions in both ip and iv approaches [88,141,142]. Recently, Uusi-Kerttula et al combined triple detargeting through mutations on the fiber that block binding to CAR, the penton to block binding to αvβ3/5 integrins, and the hexon for FX binding, with insertion of the A20 peptide into the HI loop [143].…”

Going (Reo)Viral: Factors Promoting Successful Reoviral Oncolytic Infection

“…Adenovirus (Ad5) predominantly uses the CAR receptor to mediate viral attachment and entry. The CAR receptor is rarely expressed in tumours and so adenovirus is often engineered to express differing capsid and fibre proteins (pseudotyping), facilitating entry through receptors such as CD46 that are abundant in tumours [ 55 ]. Many viruses such as Newcastle disease virus or vaccinia virus enter a cell through mechanisms such as endocytosis, and their precise receptors are presently unknown [ 42 ].…”

Treatment Modalities for the Management of Ascites in Ovarian Cancer Pa Tients

“…Due to already mentioned numerous harmful effects, the usage of these drugs is allowed, but for a limited period of time only. Contraindications are hyponatremia < 125 mmol/l, hepato-renal related decrease of sodium excretion to < 30 mmol/day, renal insufficiency with serum creatinine > 1.5 mg/dl, acute encephalopathy and acute bacterial infection (15). The use of diuretics also increases the risk of thromboembolic complications due to chemotherapy drug concentrations, and pos-sible additional symptoms include gynecomastia, renal tubular acidosis, and hyperkalemia.…”

“…Besides intraperitoneal application of cytostatics, other drugs can be used intraperitoneally, such as intraperitoneal tumor necrosis factor (TNF), interferon, and other immunomodulators (15).…”